[[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate (USAN name alvimopan) is a peripherally-acting μ opioid antagonist that is used in the treatment of post operative ileus and opioid bowel dysfunction, as well as other indications. Alvimopan is a 3,4-disubstituted-4-aryl piperidine that is a zwitterion. It has an extremely low solubility in water and many common pharmaceutically-acceptable solvents. As a result, it has poor oral bioavailability.
[[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid may exist in different crystalline forms, including hydrate forms, solvate forms and anhydrous form, and as an amorphous material. Above a relative humidity of about 15%, it exists in its crystalline dihydrate form. Below a relative humidity of about 15%, it exists in its anhydrous form. Amorphous [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid is hygroscopic and converts to its crystalline dihydrate form when it is stressed, for example, at 54% relative humidity for 12 days or 75% relative humidity in the temperature range of about 40° C. to about 80° C. for three days. Under ambient conditions, amorphous [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid completely converts to its crystalline dihydrate form after 66 days.
The crystalline dihydrate form of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid (alvimopan) has a lower solubility in water than amorphous [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid and hence lower bioavailability than the amorphous form. Accordingly, it would be desirable to develop a stable, amorphous form of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid and related 3,4-disubstituted 4-aryl piperidine derivatives. The present invention is directed to these and other important objectives.